B lymphocytes are the central players in the humoral immune response and can have both protective and pathogenic effects. Depletion of B cells is currently being investigated as a therapy for many autoimmune diseases, and has been successful in some but not all cases. A better understanding of the role of particular B cell subsets in both normal and pathological immune responses is critical for developing therapeutic approaches in which only pathogenic B cell functions are eliminated or only protective functions are stimulated. Marginal zone (MZ) B cells, an innate like B cell subset known to participate in T-independent responses, have several features that suggest functions in protective humoral immune responses, autoimmune responses, and regulatory/immunosuppressive responses. One disease in which MZ B cells may play a role is Systemic Lupus Erythematosus (SLE). This autoimmune disease is characterized by loss of tolerance to nuclear antigens, the accumulation of autoantibody (autoAb) secreting plasma cells (PCs), and the formation of immune complexes which promote inflammation and cause tissue damage. MZ B cells are enriched in autoreactive specificities. This has been proposed as a mechanism to sequester these potentially dangerous B cells away from T cells and promote B cell tolerance. However, MZ B cells differentiate rapidly into PCs and can participate in T-dependent germinal center reactions in some circumstances. Thus, it is important to understand to what degree MZ B cells contribute to autoimmune responses in lupus. Several murine lupus models have a reduction in MZ B cell numbers, which could result either from impaired development of these cells or from their enhanced differentiation into PCs. Lyn-/- and Ets1-/- mice are two such models. Interestingly, these animals accumulate PCs inappropriately, and Lyn and Ets1 are components of an inhibitory signaling pathway that normally limits PC differentiation. We hypothesize that the loss of MZ B cells in Lyn-/- mice is due to enhanced PC differentiation, and that MZ B cells contribute significantly to the accumulation of PCs and autoAbs in these mice. In Aim 1, we will ask if residual MZ B cells have a gene expression profile consistent with increased activation and PC differentiation or rather impaired commitment to or maintenance of the MZ lineage. We will also use genetic approaches to determine a) whether promoting signals required for MZ B cell development and blocking PC differentiation rescues the MZ B cell compartment in Lyn-/- mice and b) whether preventing MZ B cell development reduces PC accumulation and autoAb production in Lyn-/- mice. In Aim 2, we will generate a new mouse model expressing a MZ B cell specific Cre and use it with a Cre- reporter to mark MZ B cells and their progeny. This will be used to determine what fraction of PCs and GC B cells in Lyn-/- mice are derived from MZ B cells. This mouse model will also have many other valuable future applications, including tracking the fate of MZ derived cells in various types of immune responses and generating MZ B cell specific knockouts of genes to test their function in MZ B cell mediated processes.